The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

EMBO Rep. 2021 Oct 5;22(10):e51991. doi: 10.15252/embr.202051991. Epub 2021 Aug 5.


Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.

Keywords: mitochondria; mitochondrial quality control; peroxisomal biogenesis disorder; peroxisomal import; peroxisomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Mitochondria / genetics
  • Peroxins / metabolism
  • Peroxisomal Disorders* / genetics
  • Peroxisomal Disorders* / metabolism
  • Peroxisomes / metabolism
  • Zellweger Syndrome* / genetics
  • Zellweger Syndrome* / metabolism


  • Peroxins

Associated data

  • GEO/GSE159869